DCTD Immunotherapy Initiatives

• FY ‘ 17 - Renewal of Cancer Immunotherapy Trials

Network (CITN) - $1.5M

• FY ‘17 – FOAs: 2 RFAs– U24: Cancer Immuno-therapy Monitoring and Analysis Centers - $6.5M

– U24: Cancer Immunologic Data Commons - $1.5M

Summary of the

DCTD Cancer Immunotherapy Workshop

NCI Shady Grove, January 14-15, 2016

A 1.5-day meeting with thought leaders in the field to discuss …

• Opportunities and gaps in cancer immunology/immunotherapy

• What NCI should do to facilitate further development

Helen Chen, M.D. CTEP, on Behalf of DCTD

Speakers and invited guestsExtramural scientists

Jim Allison, MD Anderson

Ira Mellman, Genentech

Karolina Palucka, Jackson Lab

Liz Jaffee, Hopkins

Mario Sznol, Yale

Padnanee Sharma, MD Anderson

Mac Cheever, Fred Hutchinson

Biomarker/informatics experts:

Kurt Schalper, Yale

Elaine Mardis, Wash University

Lisa Butterfield, Pittsburg

Anna Wu, UCLA

Atul Butte, UCSF

Stan Hamilton, MD Anderson

Diagnostic: Adaptive, NanoString, Nodality, Immudex

Industry:

Merck, Incyte, AstraZeneca/MedImmune

NCI Intramural Scientists

Steve Rosenberg, NCI

Nick Restifo, NCI

Jay Berzofsky

Remy Bosselut

Stephen Hewitt

DCTD:

• J Doroshow, J Abrams, T Hecht

• CTEP: H Chen, H Streicher, E Sharon, J

Zwiebel

• Cancer Diagnostic Program: M Thurin

• Biologics Resource Branch: S Creekmore, A

Welch

• Radiotherapy Development Program: M

Ahmed

• BRP: R Simon

Division of Cancer Biology:

• C Marks, S McCarthy, K Howcroft, D Singer

What Should NCI Do?

Specific recommendations:

Basic science

•Mouse Models

•Tumor Microenvironment

Clinical Research

Clinical trials rich in “translation”

Clinical trials for Adoptive Cell Therapy

Biomarkers and Database

CITN AWARD to FHCRC

• A network composed of leading immunotherapists and institutions to

design and implement early phase multi-site clinical trials.

• Awarded to FHCRC/Mac Cheever, PI: Sept. 2010

• Funded the Central Operations and Statistical Center

• 3 million/yr total costs for 5 years

• Included a central Immunomonitoring Laboratory Core

• Currently 32 sites

Current CITN Trials

1. Anti‐PD1: in Merkel cell carcinoma, first systemic therapy

2. Anti‐PD1: in mycosis fungoides, advanced, treatment failure

3. Anti-PD1: for advanced malignancy in HIV+ patients

4. Anti‐CD40: in pancreas cancer, neoadjuvant

5. IL-15 (E. coli–derived, NCI): in NSCLC/H&N/renal/melanoma

6. IL-15 (IL-15/IL-15Ra/Fc fusion protein): in melanoma

7. IL-7: in prostate cancer after Provenge vaccine

8. IL-7: in glioblastoma post-temozolomide (ABTC trial; immune monitoring only)

9. IDO Inhibitor: in melanoma with MELITAC 12.1 vaccine

10. IDO Inhibitor: in ovarian cancer, neoadjuvant

11. Flt3‐Ligand + Poly ICLC + anti‐DEC205‐NY‐ESO‐1 vaccine: in melanoma,

adjuvant

2

19

28

8

17

19

60

30

24

3

0 10 20 30 40 50 60 70 80 90

CITN11-01 (Anti-CD40)…

CITN11-02 (IL15)…

CITN12-03 (IL7)…

CITN-04 (IDO-inh)…

CITN-05 (IDO-inh)…

CITN-06 (IL15Rα)…

CITN-07 (Flt3L)…

CITN-09 (Anti-PD1)…

CITN-10 (Anti-PD1)…

CITN-12 (Anti-PD1)…

NUMBER OF PATIENTS

CITN TRIALS ENROLLMENTCurrent Enrollment

Total Trial Enrollment

Key

collaborations:

Academic

(8 universities)

Government (NCI-CTEP-CITN)

Industry

(Merck)

Available on-line at NEJM.org Tuesday April 19

Responses to Pembrolizimab therapy in MCC

-40

-80

Maximum Change In Sum of Target Lesion Diameters

Pe

rce

nt C

ha

ng

e in

Ta

rge

t L

esio

ns

-10

0-6

0-2

00

20

40

60

80

(N=24)

Viral Status

Negative

Positive

100

120

140

160

Pe

rce

nt ch

an

ge

in

ta

rge

t le

sio

ns

Tumor viral statusnegative

positiven = 24

Fraction responding:44% of virus-neg62% of virus-pos

(difference not significant)

Pembrolizumab (anti-PD1) for

Merkel Cell Carcinoma• Phase II single arm, first line trial, at 7 CITN sites

• Responses (CR/PR) in 15 of 22 evaluable patients (68%); responses are rapid and appear more

durable than chemotherapy

• Presentation to European Cancer Congress, Sept. 2015; submitted “late-breaking” abstract for

April AACR presentation

• Merck is applying to FDA for “breakthrough” designation for this indication

Table 1. CITN Studies, Correlative Sciences Prioritization and Status MatrixKey: In Progress Early Stage In Progress w/o Ctrl Lab

CITN-02 CITN-03 CITN-04 CITN-05 CITN-06 CITN-07 CITN-09 CITN-10

IL-15 IL-7 iIDO/Melitac iIDO IL-15 Flt3L/CDX-1401 MK3475 MK3475

ALC ALC ALC ALC ALC ALC ALC ALC

Whole Blood

Immunophenotyping

(CS 9.2.1 and 9.2.2)

T-cell response: IFNγ

ELISPOT (CS #1)

Immunohistochemical

Evaluation of Tumor

Biopsies (9.2.1)

Immunohistochemical

Evaluation of Tumor

Biopsies (CS 9.3.1)

Whole Blood

Immunophenotyping (CS

9.2.1 and 9.2.2)

T-cell response: IFNγ

ELISPOT (CS 9.1.1)

IHC Evaluation of Tumor

Biopsiesc; Tumor PD-1 & PD-

L1 Expr (CS #1)

Kyn/Trp Ratio (Special CS

#1)

T-cell response: IFNγ

ELISPOT (CS 9.2.3)

Proliferation assay,

including Ki67 (CS #2)

Gene Expression Analyses of

Blood (9.2.2)

Intra Tumor Kyn/Trp

Ratios (CS 9.3.2)

T-cell response: IFNγ (CS

9.2.3)

Whole Blood

Immunophenotyping (CS

9.2.2)

IHC: MCPyV protein expr

(Anti-Tag); PCR: MCPyV

DNA quantification (CS #2)

Skin Biopsy Analyses

(CS #1, 2, 3)

NK cell function assays (CS

9.2.4)

Whole Blood

Immunophenotyping (CS

#3)

IFNg ELISpot (9.2.3)

Gene Expression Analyses of

Tumor Biopsies, Ascites and

PBMC (CS 9.3.3)

NK-Cell Function (CS

9.2.4)Circulating Tumor Cells (5.1)

Tetramer Phenotyping

(Flow) (CS#3); Tetramer-

sorted gene expression-

PBMC (Nanostring) (CS#4)

Gene expression (PBMC;

nanostring) (CS #3)

Serum Cytokine assays

(Elisa) (CS 9.2.5)

PAP Ab, PA2024 ELISA (CS

#4)

WB Quantification of PBMC

and T-cell Subsets (9.2.4)

T-cell response: IFNγ

ELISPOT (CS 9.3.4)

Plasma Cytokines (CS

9.2.4)

PBMC Gene Expression (CS

9.1.2)

T-cell response: IFNγ

ELISPOT: MCPyV other

tumor Ags (CD8) -(CS#5)

Whole Blood

Immunophenotyping & T

cell function assays (CS #4)

Serum IL15, IL15 Receptor

alpha and IL15 Antibody

levels (CS 9.2.6)

TREC detection (CS #5)

Intra Tumor and Plasm for

Kyn/Trp Ratios

(9.2.5)

IDO inhibitor effects on

CD8+ and CD4+ T cell

subsets (CS 9.3.5)

PK of ALT-803 (CS

9.2.6)

Antibody response: ELISA

(5.1)MCPyV Ab levels (CS #6)

Cytokine/Chemokine

Analysis (serum ELISA)

(CS #5)

TCR deep sequencing (CS

#6)

PBMC UVA Tetramer

Staining

Whole Blood

Immunophenotyping (CS

9.3.6)

Anti-CDX-1401 Abs

(NY-Eso-1) (5.1) - Both

cohorts

Whole Blood

Immunophenotyping

(CS#7)

Kyn/Trp (CS #7)TCR Repertoire (CS

9.3.7)

Anti-CDX-301 antibodies

(Flt3L) (5.1) - Cohort 1 only Kyn/Trp ratio (CS #8)

CDX301 (Flt3L) serum level

(CS 9.2.2)

Cohort 1 only

ADA CYT107

Immunogenicity (Special

Study 9.3)

INCB024360 Blood Levels

(9.3 special studies)Immunogenicity of ALT-803

IHC of T cell infiltrates

and NY-ESO-1 Expr

(CS 9.2.1)

HLA Typing FNA (T cell

characterization (Flow

Cytometry)

Circulating Tumor Cells

(CTC) (Section 11.6)

Circulating Tumor Cells

(11.3.1)Kyn/Trp Ratio

IHC of T cell infiltrates

and NY-ESO-1 Expr

(CS 9.2.1)

Circulating Sezary Cells

Lymph Node Biopsy

(Optional)

Table 1. CITN Studies, Correlative Sciences Prioritization and Status MatrixKey: In Progress Early Stage In Progress w/o Ctrl Lab

CITN-02 CITN-03 CITN-04 CITN-05 CITN-06 CITN-07 CITN-09 CITN-10

IL-15 IL-7 iIDO/Melitac iIDO IL-15 Flt3L/CDX-1401 MK3475 MK3475

ALC ALC ALC ALC ALC ALC ALC ALC

Whole Blood

Immunophenotyping

(CS 9.2.1 and 9.2.2)

T-cell response: IFNγ

ELISPOT (CS #1)

Immunohistochemical

Evaluation of Tumor

Biopsies (9.2.1)

Immunohistochemical

Evaluation of Tumor

Biopsies (CS 9.3.1)

Whole Blood

Immunophenotyping (CS

9.2.1 and 9.2.2)

T-cell response: IFNγ

ELISPOT (CS 9.1.1)

IHC Evaluation of Tumor

Biopsiesc; Tumor PD-1 & PD-

L1 Expr (CS #1)

Kyn/Trp Ratio (Special CS

#1)

T-cell response: IFNγ

ELISPOT (CS 9.2.3)

Proliferation assay,

including Ki67 (CS #2)

Gene Expression Analyses of

Blood (9.2.2)

Intra Tumor Kyn/Trp

Ratios (CS 9.3.2)

T-cell response: IFNγ (CS

9.2.3)

Whole Blood

Immunophenotyping (CS

9.2.2)

IHC: MCPyV protein expr

(Anti-Tag); PCR: MCPyV

DNA quantification (CS #2)

Skin Biopsy Analyses

(CS #1, 2, 3)

NK cell function assays (CS

9.2.4)

Whole Blood

Immunophenotyping (CS

#3)

IFNg ELISpot (9.2.3)

Gene Expression Analyses of

Tumor Biopsies, Ascites and

PBMC (CS 9.3.3)

NK-Cell Function (CS

9.2.4)Circulating Tumor Cells (5.1)

Tetramer Phenotyping

(Flow) (CS#3); Tetramer-

sorted gene expression-

PBMC (Nanostring) (CS#4)

Gene expression (PBMC;

nanostring) (CS #3)

Serum Cytokine assays

(Elisa) (CS 9.2.5)

PAP Ab, PA2024 ELISA (CS

#4)

WB Quantification of PBMC

and T-cell Subsets (9.2.4)

T-cell response: IFNγ

ELISPOT (CS 9.3.4)

Plasma Cytokines (CS

9.2.4)

PBMC Gene Expression (CS

9.1.2)

T-cell response: IFNγ

ELISPOT: MCPyV other

tumor Ags (CD8) -(CS#5)

Whole Blood

Immunophenotyping & T

cell function assays (CS #4)

Serum IL15, IL15 Receptor

alpha and IL15 Antibody

levels (CS 9.2.6)

TREC detection (CS #5)

Intra Tumor and Plasm for

Kyn/Trp Ratios

(9.2.5)

IDO inhibitor effects on

CD8+ and CD4+ T cell

subsets (CS 9.3.5)

PK of ALT-803 (CS

9.2.6)

Antibody response: ELISA

(5.1)MCPyV Ab levels (CS #6)

Cytokine/Chemokine

Analysis (serum ELISA)

(CS #5)

TCR deep sequencing (CS

#6)

PBMC UVA Tetramer

Staining

Whole Blood

Immunophenotyping (CS

9.3.6)

Anti-CDX-1401 Abs

(NY-Eso-1) (5.1) - Both

cohorts

Whole Blood

Immunophenotyping

(CS#7)

Kyn/Trp (CS #7)TCR Repertoire (CS

9.3.7)

Anti-CDX-301 antibodies

(Flt3L) (5.1) - Cohort 1 only Kyn/Trp ratio (CS #8)

CDX301 (Flt3L) serum level

(CS 9.2.2)

Cohort 1 only

ADA CYT107

Immunogenicity (Special

Study 9.3)

INCB024360 Blood Levels

(9.3 special studies)Immunogenicity of ALT-803

IHC of T cell infiltrates

and NY-ESO-1 Expr

(CS 9.2.1)

HLA Typing FNA (T cell

characterization (Flow

Cytometry)

Circulating Tumor Cells

(CTC) (Section 11.6)

Circulating Tumor Cells

(11.3.1)Kyn/Trp Ratio

IHC of T cell infiltrates

and NY-ESO-1 Expr

(CS 9.2.1)

Circulating Sezary Cells

Lymph Node Biopsy

(Optional)

CITN-05

INCB024360Correlative Sciences

Status Matrix:

Studies in Progress

Other Results in Studies to Date

• CITN-10: anti-PD1 in Mycosis Fungoides/Sezary Syndrome

– 8/24 PRs (33%) and 10/24 stable disease (42%)

– Extensive immune/genomic correlates underway

– ASH 2016 abstract planned

• CITN11-02: NCI rhIL-15 for solid tumors

– 18-fold mean increase in NK cells & 2.7-fold mean increase in CD8 T cells at 3 mg/kg, day 15

cycle 1

– Presentation at May 2016 AAI meeting

• CITN-07: DC-targeting fusion vaccine plus/minus Flt3L

– Immune response change by Flt3L primary objective

– Substantial increases in dendritic cells, NK cells, monocytes and antigen-specific T cell

responses in Flt3L-treated patients

– ASCO 2016 poster presentation

NCI-supported Immunotherapy Trials

Between 2010 -2015

• 88 Phase I-III immunotherapy trials were activated in the DCTD Clinical

Trial Network (NCTN, ETCTN, CITN, and PBTC)

• 8 Phase III trials, 14 Randomized Phase 2 trials

• Clinical settings: common, rare tumors; neoadjuvant, adjuvant and metastatic disease

• Study regimens include single agent and novel combinations

Check point inhibitors• Anti- CTLA-4 (Ipilimumab, tremelimumab)

• Anti-PD-1 (Nivolumab, Pembrolizumab)

• Anti-PD-L1 (MEDI4736 and MPDL3280A)

Cytokine:• IL-15

• IL-12

Vaccine• CDX1401 (against NYSO-1)

• PSA PROSTVAC/TRICOM

• CEA TRICOM/PANVAC

• Other: peptide (gp100, HPV, RAS, P53,

MART and others)

Oncolytic virus: • T-VEC

T-cell engaging bispecific Ab• CD19 BiTE (Blinatumomab)

Other immune modulators:• IDO (INDB0243360) ~ 2 trials

• Lenalidomide, Pomalidomide: -

• FLT3 ligands• Anti-CD27 mAb (CellDex)

Most randomized trials have mandatory collection of baseline tissues/blood

Many early clinical trials include serial biopsies

Definition of immunotherapy trials excludes MAbs directed at tumor targets or vasculature (e.g., cetuximab or bevacizumab)

Why RENEW the CITN?

• Access to immunologic agents not in DCTD portfolio (eg. anti-CD40

and IL-7),

• 40% of CITN sites are not in ETCTN providing NCI access to wider

pool of qualified immunotherapists,

• Translationally-rich trials

• Standing apparatus of immunotherapy sites is an attractive forum for

investigators, and CITN is able to rapidly take advantage of new

clinical opportunities in immunotherapy.

CITN Renewal

• Limited Competition RFA (UM1)

• Integrate into existing CTEP/ETCTN processes:

– Theradex to provide data management for all trials and

utilize CTEP CIRB

– CTSU to provide regulatory support system and website

• Subcontract/Member site composition limited to best 20 sites

• Break out immunomonitoring core to serve ALL NCI-

sponsored networks/consortia (ie. CITN, ETCTN, ABTC and

early NCTN trials) as a SEPARATE Network through a

SEPARATE RFA

Next Directions in the CITNFocus on Combinations (NCI-held or not held)

IL-15:

• Combinations:

– IL-15 plus monoclonal antibody for enhanced ADCC (eg. with cituximab)

– IL-15 with anti-PD1 (Merck)

• Admune/Novartis IL-15 fusion protein with NCI CCR (expansion cohort)

Other anti-PD1 trials:

• Anti-PD1 plus IL-7 (Merck and Revimmune)

• Anti-PD1 failures – to biopsy, assess actionable reasons for failures

Other combinations:

• Anti-CD137 (4-1BB) plus trastuzumab (Pfizer) in breast cancer

• Intratumoral anti-CTLA4 plus local radiation plus anti-PD1 (Merck)

CITN UM1 Budget

Operations and Statistical Office $350K

Scientific Leadership 50K

Network Meetings and travel 30K

Treatment site support* 720K

Total Direct 1150K

Total Costs 1500K

*assume 120 patients/yr at $6,000/patient

Extra Slides

Review of CITN by an External Panel• Panel: Immunotherapy experts (5) plus medical oncologists outside of immunotherapy (2);

Dr. Kim Lyerly, chair

• Overall recommendation (unanimous): support recompetition

– Stellar team of investigators at major US immunotherapy sites

– An infrastructure for coordinated areas of inquiry with a primary focus on

immunotherapy, and for high quality and uniformed immunological assessment with

the potential to expand the sophistication of analysis

– Trial selection overall consistent with the aims of the network

– Accrual appropriate given the focus on immunotherapy, emerging organizational

capabilities, and need to address both CTEP and industry requirements

– Enhances the existing clinical trials infrastructure and developmental therapeutics

programs at the NCI

– Well poised to make contributions in the future

Recommendations

• Infrastructure can be rate limiting as more protocols come on line:

to increase efficiency, restructure to utilize the established

infrastructure in CTEP

• Sites that are also ETCTN sites should engage appropriate

investigators outside of the immunotherapy realm for testing

combinations of targeted drugs with immuno-oncology agents

• Broaden leadership perspectives for decisions about future CITN

trials